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Antidepressants in Inflammatory Bowel Disease: A Systematic Review

Macer, Benjamin J. D. MSc; Prady, Stephanie L. PhD; Mikocka-Walus, Antonina PhD

doi: 10.1097/MIB.0000000000001059
Clinical Review Articles

Background: Antidepressants are commonly used to treat symptoms of anxiety and depression in inflammatory bowel disease (IBD). Recent studies suggest a link between IBD activity and an individual's emotional state which raises the possibility that antidepressants may potentially modify the disease course of IBD. This systematic review thus primarily aims to evaluate the efficacy of antidepressants on IBD activity, and secondarily, on anxiety and depression.

Methods: MEDLINE, EMBASE, Cochrane (IBD Group), CINAHL, AMED, PsycINFO, and OpenGrey were searched from 1990 onward with no restrictions on study design. A quality appraisal was conducted using several scales as appropriate for each study design. A narrative synthesis was also conducted.

Results: Fifteen eligible studies included in the review (1 randomized controlled trial, 2 cohorts, 1 case–control, 1 cross-sectional survey, 1 qualitative, 2 audits, 1 case series, and 6 case reports) examined a range of antidepressants. Twelve studies suggested that antidepressants have a positive impact on IBD course. Nine studies reported anxiety and depression as an outcome, of these 8 reported beneficial effects of antidepressants. Most of the studies were deemed to be at low risk of bias, apart from the case reports, which were at high risk of bias.

Conclusions: This research indicates that antidepressants may have a beneficial effect on IBD course. However, it is currently not possible to determine their efficacy for certain because of the lack of randomized trials. Further trials using objective measures of IBD activity, longer follow-up periods, and larger sample sizes are needed.

Published online 9 March 2017

*Department of Health Sciences, University of York, York, United Kingdom; and

School of Psychology, Deakin University, Burwood, Victoria, Australia.

Address correspondence to: Antonina Mikocka-Walus, PhD, School of Psychology, Deakin University, 221 Burwood Highway, Burwood, 3125 Victoria, Australia (e-mail: mikocka@deakin.edu.au).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

The authors have no conflict of interest to disclose.

Received November 14, 2016

Accepted January 17, 2017

Depression and anxiety have a negative effect on disease course in inflammatory bowel disease (IBD). A recent systematic review of 86 studies found that adults with IBD are more likely to develop anxiety and depression before IBD onset, and rates of anxiety and depression are higher in patients with IBD than in the general population, and higher in those with active IBD compared with inactive IBD (66.4% versus 28.2% respectively for anxiety, and 34.7% versus 19.9% for depression1).

Antidepressants are often used to treat the anxiety and depression that is commonly experienced by patients with IBD, a case-note audit found that 28.9% of patients with IBD in a public tertiary hospital had used antidepressants at some point in their life.2 Antidepressants have also been shown to be effective in treating gastrointestinal symptoms associated with some other disorders. A systematic review and meta-analysis looking at the effect of antidepressants and psychological therapies on irritable bowel syndrome, a functional gastrointestinal disorder, found antidepressants to have efficacy over placebo in the improvement of somatic bowel symptoms (relative risk 0.67; 95% CI, 0.58–0.77) with similar effects observed for both selective serotonin reuptake inhibitors and tricyclic antidepressants.3 A systematic review of animal models of colitis has found that desipramine and fluoxetine reduce the risk of colitis and improve inflammatory markers, with little evidence of adverse effects.4

A previous systematic review published 10 years ago examined the effect of antidepressants in the treatment of IBD and found 12 publications, none of which were randomized controlled trials (RCTs).5 The review suggested that 16/20 patients experienced beneficial effects on physical IBD symptoms as a result of antidepressants, but conclusions were limited because of the observational nature of the research and very small samples of patients.

Given that psychological factors play an important role in IBD activity and antidepressants have been reported to have anti-inflammatory properties6,7, antidepressants have the potential to be an adjuvant treatment for IBD. Despite the lack of conclusive evidence on efficacy or effectiveness, antidepressants are already prescribed in the treatment of somatic IBD symptoms2 and thus it is timely to review the role they may play in IBD management.

The aim of this study is to (1) examine the evidence on the impact of antidepressants on disease activity, and (2) their impact on comorbid symptoms of anxiety and depression in IBD.

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MATERIALS AND METHODS

Search Strategy

We searched MEDLINE, EMBASE, Cochrane (Cochrane Inflammatory Bowel Disease and Functional Bowel Disease Group), CINAHL, AMED, and PsycINFO. Search strategies were compiled with the assistance of an academic librarian. Articles published before 1990 were not included. No restrictions were placed on language during the searches although for practical reasons, it was only possible to include English language articles. An example search strategy is presented in the Appendix, Supplemental Digital Content 1, http://links.lww.com/IBD/B467. Searches were conducted on third June 2016 by one author (B.J.D.M.).

The reference lists of included articles were scanned and 1 journal (Gastroenterology) hand searched. Titles and abstracts of retrieved studies were screened for inclusion. The full text of potentially relevant articles was obtained, and the inclusion and exclusion criteria were applied.

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Inclusion Criteria

Studies were included if they met the following criteria:

1. Contained human participants, clinically diagnosed with any form of IBD (i.e., Crohn's disease [CD], ulcerative colitis [UC], or intermediate colitis based on clinical, histological, radiological, or endoscopic criteria).

2. Participants could be any age and any sex.

3. Participants were prescribed or took any of the following antidepressants: tricyclics, monoamine oxidase inhibitors, serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, or atypical antidepressants. Antidepressants could be used both with and without other treatments, apart from other pharmacological psychiatric treatments (such as anxiolytics). Standard care was assumed.

4. Any comparator.

5. Any study design.

6. Contained an outcome measure of remission or anxiety/depression outcome (see Outcome Measures below).

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Exclusion Criteria

1. Participants were prescribed or took any other form of medication used to treat depression or anxiety; such as herbal medicines and anxiolytics alone.

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Outcome Measures

For studies to be included in the review, they had to include at least 1 of the following primary or secondary outcomes:

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Primary Outcome

1. Remission measured through changes in disease activity indices as per respective cut-off values, as defined by study authors (e.g., Crohn's Disease Activity Index [CDAI], Simple Clinical Colitis Activity Index [SCCAI]), using calprotectin, colonoscopy, or other similar measures (e.g., blood).

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Secondary Outcomes

1. Anxiety and depression symptoms, as measured through using any relevant diagnostic interview technique or screening scale.

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Data Extraction

Data pertaining to the sample, methods, and results were extracted from each of the included studies by 1 author (BJDM).

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Quality Assessment

Other than human participants this review applied no restrictions on study design; therefore, the variety of study designs necessitated the use of several different quality assessment tools. The Cochrane Risk of Bias tool was used for randomized trials;8 this was based on 8 questions which can be addressed with either “Low risk” or “High risk.” The Newcastle–Ottawa Scale (NOS) was used for observational studies (case–control and cohorts),9 for which a study can score a possible of 8 points, a higher score signifies a lower risk. The National Institute of Health (NIH) quality assessment tool was used for audits, case reports, and case series.10 Another NIH quality assessment tool was used to assess the quality of cross-sectional surveys.11 Both of the NIH tools used gave a final quality rating of “Good,” “Fair,” or “Poor.” Qualitative studies were assessed using the Critical Appraisal Skills Programme (CASP) tool.12 The CASP tool has 10 questions which can be answered “Yes,” “Can't tell,” or “No”; a “Yes” would imply a low risk of bias.

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Data Analysis

A narrative synthesis was used to describe and compare the studies. A meta-analysis was planned but not performed because of heterogeneity of study design and outcomes.

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RESULTS

A total of 2193 studies were retrieved with 1840 screened after duplicates were removed (Fig. 1). Fifteen studies were included in the review: 1 placebo-controlled RCT, 1 prospective and 1 retrospective cohort study, 1 retrospective case–control study, 1 cross-sectional survey, 1 qualitative study, 1 report on a clinical case note audit, 1 audit, 1 case series, and 6 case reports. The follow-up period of the studies varied from 6 weeks to 11 years. The majority of the studies were from the United States (n = 8) and Australia (n = 3), with 1 study each from England, Iran, New Zealand, and India.

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Quality Assessment

Quality assessments of each individual study are shown in Tables 1–4. The RCT13 was at low risk of bias with only high-risk scores from the sections assessing attrition bias.

Using the NOS for nonrandomized studies, Yanartas et al. (2016) was at low risk of bias, and Iskandar et al (2014) was at mid-to-high risk of bias, primarily because it contained an irritable bowel syndrome comparative cohort which was irrelevant for this review. The case–control study14 was deemed to be at low risk of bias. The main weakness of this study was the representativeness of the participants because they were sampled from a single tertiary care IBD center in London. In the cross-sectional survey,15 6 of the 7 relevant categories received a “Yes” on the NIH tool. The reasons for not receiving a “Yes” on the other category were because it was not possible to determine if 50% of eligible persons took part in the study. The study was given an overall quality rating of “Good” indicating a low risk of bias. The single qualitative study16 met all the 9 criteria as set out by the CASP assessment tool, and the study was deemed to be at low risk of bias.

The NIH tool was used to quality assess the 2 audits, the case series, and the 6 case reports. The report on a case note audit2 met all the criteria apart from length of follow-up, as this was not applicable; scoring “Good” overall deeming it at low risk of bias. The other audit17 was deemed at high risk of bias, only receiving a “Yes” in 3 of the 9 categories.

The case series18 was at low risk of bias only being marked down because the length of follow-up was inadequate. Of the case reports the study quality was generally poor, so a high risk of bias. A weakness of all the case reports, of which 2 were abstracts, is that the outcome measures were not clearly defined, with often incompletely reported results.

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Narrative Synthesis

Of the 15 included studies, 14 (93%) addressed the primary outcome measure of remission and 10 (67%) addressed the secondary outcomes of anxiety/depression. See Table 5 for a description of each study and Table 6 for results.

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RCT

The RCT was conducted between 2013 and 2014 in Iran.13 Forty-four participants were randomly allocated to either be prescribed duloxetine (60 mg once a day) or a placebo for 12 weeks. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) and symptom severity using Lichtiger Colitis Activity Index (LCAI). Five patients were lost to follow-up in the intervention group and 4 in the control group, leaving a total of 35 participants (UC: 22; CD: 13) in the analysis.

Symptom severity significantly improved in the intervention group compared with the control group (P = 0.02). Depression and anxiety also improved significantly in the intervention group compared with the control group (depression P = 0.041; anxiety P = 0.049).

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Cohorts

The retrospective cohort study included 81 participants taking tricyclic antidepressant (UC: 23; CD: 58)19 who were followed over 11 years using outpatient records from a Gastroenterology practice in St. Louis, Missouri. Baseline symptom severity was assessed on a 4-point Likert scale (0 = no symptoms to 3 = severe, disabling symptoms) with no significant difference between disease types. Antidepressant treatment responses were graded using an established 4-point scale (0 = no improvement to 3 = complete satisfaction). Patients with UC responded significantly better than patients with CD at first follow-up (time frame not stated), mean 1.86 (SEM 0.13) for UC and 1.26 (0.11) for CD (P = 0.003). Eighty-three percent of patients with UC had at least a moderate symptomatic improvement on tricyclic antidepressant, compared with 50% of patients with CD (P = 0.01). At the second follow-up (time frame not stated), there was no significant difference between the disease types (CD: 1.31 [SEM 0.16]; UC: 1.47 [0.17], P = 0.76) or on whether they had at least a further moderate symptom response, (CD 56%; UC 40% P = 0.16).

The prospective study20 followed 67 patients (UC: 36; CD: 31) from an IBD-specific Gastroenterology outpatient clinic at a hospital in Istanbul, between June 2013 and June 2014. The CDAI and Modified Mayo Score (MMS) were used to measure disease activity for CD and UC, respectively, as well as C-reactive blood count. Anxiety and depression were assessed using HADS and Structured Clinical Interview for DSM Disorders (SCID-I).

Antidepressant treatment was not associated with a significant improvement in CDAI compared with the control group (mean improvement −62.9 [SD: 99.5], P = 0.57), nor was it associated with improvement in MMS (−1.6 [3.4], P = 0.926). However, a significant improvement was seen in anxiety and depression when compared with the control group, P = 0.001 and P = 0.017, respectively.

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Case–control Study

The case–control study retrospectively compared 58 participants, 29 (UC: 14; CD: 15) who were sampled from an adult and pediatric IBD center in London, United Kingdom.14 In the intervention group (n = 29), antidepressants were used to treat mood disorders; the matched controls (n = 29) received no antidepressants therapy; patients were matched based on age, sex, disease type, medication at baseline, and relapse rate in year 1. Patients were assessed the year before and the year after initiation of antidepressant therapy.

Outcomes included number of relapses, number of endoscopic procedures, number of outpatient attendances and hospital admissions, and number of courses of steroids. Fewer relapses and courses of steroids in the year after starting an antidepressant were experienced in the intervention group than in the year before {1 (0–4) (median [range]) versus 0 (0–4), P = 0.002; 1 (0–3) versus 0 (04), P < 0.001, respectively}. The controls showed no changes between years 1 and 2 in relapses (1 [0–4] versus 1 [0–3], respectively) or courses of steroids (1 [0–2] versus 0 [0–3]). There was a significant difference between the 2 groups for number of relapses (P = 0.03), but not for course of steroids (P = 0.07).

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Cross-sectional Survey

The cross-sectional on-line survey, advertised between March 2012 and April 2013, included 98 participants (UC: 32; CD: 48; intermediate colitis: 3; missing type: 15) from a nonclinical population recruited through the Australian IBD advocacy and support group.15 Participants were required to be taking antidepressants or had previously been on antidepressants since their IBD diagnosis. The aim of the study was to explore the use and type of antidepressants currently prescribed to IBD sufferers, their effects on symptoms, and experiences of them.

Participants had been taking antidepressants for an average of 4 (SD: 3.9) years, with a range of 4 weeks to 15 years. Of those individuals taking antidepressants, 79% reported perceived improvements; however, 67% had observed no change in perceived disease activity. Disease activity was found to improve in 25% of participants. The study also showed perceived psychological well-being had improved in 87% of participants.

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Qualitative Study

The qualitative study interviewed 15 participants taking antidepressants, sampled from The Royal Adelaide Hospital, a tertiary teaching hospital in South Australia.16 The interviews, conducted between January and March 2011, were semistructured, containing open-ended questions relating to IBD history, reasons for antidepressant therapy and details of the therapy, acceptance of the treatment, side effects, impact on IBD and quality of life, and attitudes toward taking part in future trials.

The study showed that antidepressants helped disease course (n = 5), reduced pain and frequency of bowel movements (n = 3), and reduced the frequency of symptoms or flare up (n = 3). Conversely, n = 10 reported that antidepressants did not influence disease course, although the authors did concede that it was difficult to distinguish between the effectiveness of different treatments. The study also showed that the majority of the participants had a positive attitude toward antidepressants (n = 9). Twelve of the participants stated they would take part in further trials; 2 did not want to change their antidepressant treatment because of their success with it.

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Audits

The case-note audit was conducted at the center where the participants from the qualitative study, mentioned above, were sampled. This retrospective analysis was from an IBD database at an Australian tertiary hospital, and assessed participants for type, frequency, and impact of antidepressant therapy on IBD course.2

The audit showed that from 287 participants (UC: 95; CD: 179; intermediate colitis: 13), 51 (18%) were currently taking antidepressants. Within the 51 taking antidepressants, 15 (30%) individuals had inactive disease but presented with symptoms such as pain or diarrhea, consistent with functional bowel disorders, 11 (22%) were in full remission with no disease activity, 2 (0.01%) had active disease, and the data for 23 (45%) participants were not recorded. Seventy-one patients had a history of antidepressant use, 45 (63%) were prescribed for anxiety and depression, or both; 10 (14%) were for somatic complaints, and no data were available for the remaining 16 (22.5%) patients. While on antidepressants, 19 (28%) had inactive disease but had functional symptoms; 12 (17%) had active disease; and 9 (13%) had inactive disease.

The other study (reported as an abstract)17 we have classified as an audit but may be better described as a series of annually conducted cross-sectional surveys of patient IBD activity and antidepressant use in an IBD clinic. The results showed that in 855 IBD participants (UC: 352; CD: 503), the mean IBD activity decreased over 4 years, independent of serotonin reuptake inhibitor use.

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Case series

The one case series included18 studied 8 IBD participants from a Gastroenterology tertiary care center in Seattle, attending from March to October 1993. Participants were screened and selected if they were diagnosed with major depression, using Hamilton Depression Rating Scale and Structured Clinical Interview for DSM Disorders.

Participants were interviewed at baseline using the National Institute of Mental Health (NIMH) Diagnostic Interview Schedule for Children (DISC), a structured interview process used to determine current and lifetime diagnoses of a number of psychiatric disorders. Participants also had gastrointestinal symptom interviews.

All participants were then treated with paroxetine and received follow-up interviews at 8 weeks. Disease activity was not reported in the study. Depression improved significantly when comparing participant's pre- and post-data, P = 0.0001 (pretreatment 29.0 [SD 7.7]; posttreatment 8.1 [6.1]).

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Case Reports

Of the 6 included case reports,21–26 2 were reported as abstracts only,25,26 1 of the case reports describes an individual with UC,25 and the rest of the studies refer to patients with CD. The patient with UC had generalized anxiety disorder and was treated with mirtazapine (15 mg) at night and after 6 weeks had relief from bloody diarrhea, rectal pain, and anxiety. The other abstract described a 64 year-old-man with 6 months of 4 to 6 watery bowel movements per day.26 The patient was receiving mirtazapine and sertraline for severe depression; when the dosage was changed to be taken at night, the patient had relief from IBD symptoms.

One case report found phenelzine to reduce bowel movements from 10 watery movements per day to one soft movement per day and without any cramping.22 The participant was tapered off any other medications, and the symptoms only returned when phenelzine was stopped after 2 years. Another report found no improvements on IBD course after treatment with transdermal amitriptyline; however, no adverse effects were observed.24 The 2 remaining studies reported CDAI; in both these studies, all the patients (n = 6) achieved remission with antidepressant treatment.21,23

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DISCUSSION

Most studies (80%) included in this systematic review reported antidepressants to have a beneficial effect on IBD course, and 60% reported a beneficial effect on anxiety and depression levels. Despite this encouraging finding, due to the limitations of the observational study designs included, no firm conclusions can be drawn about the efficacy or effectiveness of antidepressants in IBD. Nevertheless, judging by the success of antidepressant treatment in functional gut disorders and particularly the improvements in bowel functions and abdominal pain,3,27 but also by a significant proportion of patients with IBD actively using antidepressants (between 10% and 30%)2,28,29 antidepressants have a role to play in IBD management. Whether this is because they influence the inflammatory processes or simply because they improve mood is hard to decipher at present, and their role in IBD should be further investigated.

To the authors' knowledge, only one other similar systematic review has been conducted.5 The systematic review included 12 relevant articles; however, the authors found a paucity of high-quality data. None of the included articles were RCTs; 5 of them were not primary research and the same group conducted 7 of the studies. The previous review, while acknowledging the poor methodological quality of the included studies, concluded that the results suggest that antidepressants have the potential to be used to help certain individuals cope with the emotional comorbidities of IBD; such as anxiety and depression, improve quality of life, and possibly have a beneficial effect on the IBD course. In the 10 years since this review was conducted, the evidence seems to have improved slightly. One RCT was included in this review but it had some limitations which may have biased the results. It should be noted that another small trial has been published in recent weeks,30 reporting no impact of fluoxetine on disease activity over 12 months in CD but observing some potentially positive impact of this antidepressant on the cytokine profiles.

There is much speculation around the potential mechanism of action of antidepressants in altering the course of IBD. Three of the included studies13,14,20 hypothesized that the improvements seen in patients could be because of the anti-inflammatory properties observed in antidepressants.31 There is evidence that antidepressants can lower circulating levels of tumor necrosis factor–alpha and this could potentially explain the positive effects of antidepressants on IBD course.32,33 Alternatively, and most probably, improvements seen can be a direct result of the reduction in the symptoms of anxiety and depression as a result of antidepressants. The brain–gut–microbiome research reviewed elsewhere points toward this explanation.34–36 However, further research is required to conclusively determine the exact mechanism or mechanisms of action.

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Current Guidelines

A recent review of the international evidence-based guidelines on managing IBD and its comorbid psychosocial issues37 concluded that psychological distress should be screened for and treated appropriately, with psychotherapy/psychopharmacotherapy offered if required. The dominance of observational studies in this review precludes a judgment on the efficacy of antidepressants on IBD course, but results indicate the possibility of an effect which needs experimental verification.

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Limitations of Included Studies

The majority of the included studies were observational, uncontrolled, and nonrandomized. Only 3 studies had follow-up periods at 2 years or more, 5 studies had follow-up periods of 12 weeks or less. IBD often takes longer than 12 months to go through cycles of relapse and remission. Population-based studies have shown that after 5 years of being diagnosed as in remission, nearly 100% of patients have relapsed;38 therefore, follow-up periods that are shorter than this are not likely to capture long-term effectiveness.

Many of the studies had small sample sizes and only sampled participants from a single source; therefore, participants are unlikely to be representative of the IBD population as a whole. Furthermore, all studies did not account for differences by sex in their analyses, which is important because women may be at greater risk of anxiety and depression than men.39

The final limitation of the included studies is the study design. Only 1 RCT was included and 6 (40%) were case; 2 studies were incompletely reported conference abstracts.

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Strengths and Limitations of This Review

There were a number of strengths to this review, the first being its comprehensive literature search which included an extensive search string and a large number of databases, including gray literature. The review was also adapted to account for the differing study designs using a range of quality assessment tools.

Despite these strengths, there were a number of limitations to the review. Because of the limited resources, it was not possible to have a second reviewer at either the screening or data extraction stages of the review. The review was also limited by only including articles published in English. However, only 30 non-English publications were excluded and based on the percentage of relevant English articles once titles and abstracts were screened (2.9%), it would be unlikely that the non-English language publications would have yielded further studies.

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Future Research

Further RCTs are required to improve understanding of the impact of antidepressants on IBD course. Trials should aim to recruit larger numbers of participants, and analyses should take account of potential sex differences. Future trials should also prioritize objective measures of disease activity (i.e., calprotectin, colonoscopy) over subjective (i.e., disease activity indices) when assessing IBD activity.

The previous systematic review5 recommended that future research should differentiate between CD and UC; this recommendation has not changed in light of this review findings. Finally, longer follow-up periods (at least 5 years) are required to more accurately determine the efficacy of antidepressants therapy on disease course.

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CONCLUSIONS

Antidepressants are commonly used by patients with IBD; however, based on the findings from this systematic review, it is not possible to determine for certain whether antidepressants have a beneficial effect on the course of IBD. The state of research has improved over the last 10 years; however, nearly all the evidence comes from observational studies where cause and effect are difficult to attribute. Further properly conducted RCTs with validated measures, larger samples, and adequate follow-up periods are required to accurately determine the efficacy of antidepressants on improving disease course.

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ACKNOWLEDGMENTS

We are very grateful to David Brown, Academic Liaison Librarian at the University of York for his help in compiling the search strategy.

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Keywords:

antidepressants; anxiety; depression; inflammatory bowel disease; systematic review

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